Dry eye, a group of disorders that affects ~5 million people over the age of 50 in the USA today, is characterized by inadequate hydration and lubrication of the ocular surface. The final common pathway for all types of dry eye is disruption of the ocular surface barrier, which can be assessed by quantifying uptake of water-soluble dyes applied topically to the ocular surface. In preliminary data using a preclinical model, it is shown that topical delivery of clusterin (CLU), a natural homeostatic tear protein, prevents and ameliorates barrier disruption in a preclinical model by a remarkable sealing mechanism dependent on attainment of a critical all-or-none threshold. The anti-inflammatory, proteostatic and cytoprotective activities of CLU are well known. It is shown that CLU binds to the ocular surface subjected to desiccating stress selectively and positioned in this way, it also protects barrier structure. The long-term goal of Proteris Biotech, Inc. is to translate CLU to the clinic a an FDA-approved biotherapeutic. This Phase I STTR application has two immediate scientific goals: 1) to establish and perform good manufacturing practices (GMP)-compatible production of a human recombinant form of CLU, called Protearin, under non-GMP conditions; 2) to demonstrate that Protearin is functionally equivalent to human plasma-derived CLU and compare its efficacy to two reference compounds. In addition, planning activities for STTR Phase II will be performed including, 1) writing a protocol to transfer the process for Protearin production to a GMP lab, and for adapting to GMP compliance; 2) identifying a qualified subcontractor for Good Laboratory (GLP) testing of GMP-produced Protearin; 3) writing a protocol for a first-in-human phase I clinical trial of Protearin, the goal to assess product safty and provide proof-of-principal of efficacy in humans; 4) recruiting collaborators/consultants and searching for new lab space for executing these next steps. Most efforts for new drug development in the DE arena have been devoted to targeting of inflammation, tear production, tear film movement and tear chemistry, i.e., factors located upstream in the cascade of events leading to DE and OCS disruption. These factors differ and the various types of dry eye. CLU's action in sealing at the OCS has not been described for any other drug under development. A therapeutic that can target upstream factors in dry eye, as well as barrier disruption, the final common endpoint, represents an important innovation.